m6A and YTHDF proteins contribute to the localization of select neuronal mRNAs

Nucleic Acids Research, Год журнала: 2022, Номер 50(8), С. 4464 - 4483

Опубликована: Апрель 14, 2022

The transport of mRNAs to distal subcellular compartments is an important component spatial gene expression control in neurons. However, the mechanisms that mRNA localization neurons are not completely understood. Here, we identify abundant base modification, m6A, as a novel regulator this process. Transcriptome-wide analysis following genetic loss m6A reveals hundreds transcripts exhibit altered hippocampal Additionally, using reporter system, show mutation specific sites select neuronal diminishes their neurites. Single molecule fluorescent situ hybridization experiments further confirm our findings and reader proteins YTHDF2 YTHDF3 mediators effect. Our reveal function for controlling enable better understanding through which influences brain.

Язык: Английский

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Prediction of RNA–protein interactions using a nucleotide language model

Bioinformatics Advances, Год журнала: 2022, Номер 2(1)

Опубликована: Янв. 1, 2022

The accumulation of sequencing data has enabled researchers to predict the interactions between RNA sequences and RNA-binding proteins (RBPs) using novel machine learning techniques. However, existing models are often difficult interpret require additional information sequences. Bidirectional encoder representations from transformer (BERT) is a language-based deep model that highly interpretable. Therefore, based on BERT architecture can potentially overcome such limitations.

Язык: Английский

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High level of novelty under the hood of convergent evolution

Science, Год журнала: 2023, Номер 379(6636), С. 1043 - 1049

Опубликована: Март 10, 2023

Little is known about the extent to which species use homologous regulatory architectures achieve phenotypic convergence. By characterizing chromatin accessibility and gene expression in developing wing tissues, we compared architecture of convergence between a pair mimetic butterfly species. Although handful color pattern genes are be involved their convergence, our data suggest that different mutational paths underlie integration these into development. This supported by large fraction accessible being exclusive each species, including de novo lineage-specific evolution modular optix enhancer. These findings may explained high level developmental drift evolutionary contingency occurs during independent mimicry.

Язык: Английский

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UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability

Molecular Cell, Год журнала: 2023, Номер 83(15), С. 2753 - 2767.e10

Опубликована: Июль 20, 2023

Nuclear hormone receptors (NRs) are ligand-binding transcription factors that widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. is critical for therapeutic efficacy in malignancies driven retinoic acid estrogen receptors. Here, we demonstrate the UBR5 drives of multiple agonist-bound NRs, including receptor alpha (RARA), retinoid x (RXRA), glucocorticoid, estrogen, liver-X, progesterone, vitamin D We present high-resolution cryo-EMstructure full-length human a negative stain model representing its interaction with RARA/RXRA. ligands induce sequential, mutually exclusive recruitment nuclear coactivators (NCOAs) to chromatin regulate transcriptional networks. Other pharmacological such as selective degraders (SERDs) degrade their through differential or RNF111. establish regulatory hub common mediator regulator NR-induced transcription.

Язык: Английский

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Determinants of substrate specificity in a catalytically diverse family of acyl-ACP thioesterases from plants

BMC Plant Biology, Год журнала: 2023, Номер 23(1)

Опубликована: Янв. 2, 2023

ACYL-LIPID THIOESTERASES (ALTs) are a subclass of plastid-localized, fatty acyl-acyl carrier protein (ACP) thioesterase enzymes from plants. They belong to the single hot dog-fold family. ALT generate medium-chain (C6-C14) and C16 acids, methylketone precursors (β-keto acids), 3-hydroxy acids when expressed heterologously in E. coli. The diverse substrate chain-length oxidation state preferences ALTs set them apart other plant acyl-ACP thioesterases, show promise as metabolic engineering tools produce high-value methylketones bacterial or systems. Here, we used targeted motif-swapping approach explore connections between sequence specificity. Guided by comparative motif searches computational modelling, exchanged regions amino acid ALT-type thioesterases Arabidopsis thaliana, Medicago truncatula, Zea mays create chimeric proteins.Comparing activity profiles coli their wild-type counterparts led identification interacting within domain that shape specificity enzyme activity. Notably, presence 31-CQH[G/C]RH-36 on central α-helix was shown shift towards 12-14 carbon chains, be core determinant with preference for 3-hydroxyacyl- β-ketoacyl-ACP substrates. For an containing this functional, additional 108-KXXA-111 compatible spanning aa77-93 surrounding β-sheet must also present, demonstrating interactions residues these catalytic critical behaviour indicated play significant role dictating whether will prefer ≤10-carbon ≥ 12-carbon acyl chain-lengths, aa91-96 influence selectivity substrates fully partially reduced states. Additionally, aa64-67 were important enabling act substrates.By revealing specificity, study is advancement recombinant product suited specific applications.

Язык: Английский

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ExplaiNN: interpretable and transparent neural networks for genomics

Genome biology, Год журнала: 2023, Номер 24(1)

Опубликована: Июнь 27, 2023

Deep learning models such as convolutional neural networks (CNNs) excel in genomic tasks but lack interpretability. We introduce ExplaiNN, which combines the expressiveness of CNNs with interpretability linear models. ExplaiNN can predict TF binding, chromatin accessibility, and de novo motifs, achieving performance comparable to state-of-the-art methods. Its predictions are transparent, providing global (cell state level) well local (individual sequence biological insights into data. serve a plug-and-play platform for pretrained annotated position weight matrices. aims accelerate adoption deep analysis by domain experts.

Язык: Английский

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The splicing regulators RBM5 and RBM10 are subunits of the U2 snRNP engaged with intron branch sites on chromatin

Molecular Cell, Год журнала: 2024, Номер 84(8), С. 1496 - 1511.e7

Опубликована: Март 26, 2024

Understanding the mechanisms of pre-mRNA splicing is limited by technical challenges to examining spliceosomes in vivo. Here, we report isolation RNP complexes derived from precatalytic A or B-like solubilized chromatin pellet mammalian cell nuclei. We found that these contain U2 snRNP proteins and a portion snRNA bound with protected RNA fragments precisely map intronic branch sites across transcriptome. These also contained regulators RBM5 RBM10. RBM10 nearly all site not simply those at regulated exons. The deletion conserved RBM5/RBM10 peptide sequence, including zinc finger motif, disrupted interaction rendered inactive for repression many alternative propose model where regulate as components complex following base pairing.

Язык: Английский

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Species-aware DNA language models capture regulatory elements and their evolution

Genome biology, Год журнала: 2024, Номер 25(1)

Опубликована: Апрель 2, 2024

Abstract Background The rise of large-scale multi-species genome sequencing projects promises to shed new light on how genomes encode gene regulatory instructions. To this end, algorithms are needed that can leverage conservation capture elements while accounting for their evolution. Results Here, we introduce species-aware DNA language models, which trained more than 800 species spanning over 500 million years Investigating ability predict masked nucleotides from context, show models distinguish transcription factor and RNA-binding protein motifs background non-coding sequence. Owing flexibility, conserved much further evolutionary distances sequence alignment would allow. Remarkably, reconstruct motif instances bound in vivo better unbound ones account the evolution sequences positional constraints, showing these functional high-order context. We training yields improved representations endogenous MPRA-based expression prediction, as well discovery. Conclusions Collectively, results demonstrate a powerful, flexible, scalable tool integrate information large compendia highly diverged genomes.

Язык: Английский

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Detection of newly synthesized RNA reveals transcriptional reprogramming during ZGA and a role of Obox3 in totipotency acquisition

Cell Reports, Год журнала: 2024, Номер 43(4), С. 114118 - 114118

Опубликована: Апрель 1, 2024

Zygotic genome activation (ZGA) after fertilization enables the maternal-to-zygotic transition. However, global view of ZGA, particularly at initiation, is incompletely understood. Here, we develop a method to capture and sequence newly synthesized RNA in early mouse embryos, providing transcriptional reprogramming during ZGA. Our data demonstrate that major ZGA gene begins earlier than previously thought. Furthermore, identify set genes activated minor promoters which show enrichment Obox factor motif, find Obox3 or Obox5 overexpression embryonic stem cells activates genes. Notably, expression factors severely impaired somatic cell nuclear transfer (SCNT) restoration corrects profile greatly improves SCNT embryo development. Hence, our study reveals dynamic underscores crucial role facilitating totipotency acquisition.

Язык: Английский

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AIRE relies on Z-DNA to flag gene targets for thymic T cell tolerization

Nature, Год журнала: 2024, Номер 628(8007), С. 400 - 407

Опубликована: Март 13, 2024

Язык: Английский

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